Method of alkylating esters



United States Paten METHOD or ALKYLATING asraas Harold E. Zaugg, Lake Forest, Floyd C. Garveu, Gurnee, Adolph 0. Geiszler, Mundelein, and Kenneth E. Hamlin, Lake Bluff, Iil., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed June 18, 1958, Ser. No. 742,736

7 Claims. (Cl. 260-485) This invention relates broadly to an improved method of introducing a hydrocarbon group into an organic compound of the class exemplified by malonic ester, acetoacetic ester, other S-keto esters and a-cyano esters which have an active hydrogen atom and more particularly to an improved method of introducing an alkyl, an alkenyl, an aralkyl, or aryl group into compounds of the class exemplified by malonic ester, acetoacetic esters, other B-keto esters and u-cyanoesters at a carbon atom thereof having an active hydrogen and which is also alkyl substituted.

Heretofore the organic compounds to be alkylated, alkenylated or aralkylated were converted to the metallo derivative and to a solution of said derivative'in an alcoholic or hydrocarbon solvent was then added the ap propriate halide or disulfate and the reaction mixture heated, usually at refluxing temperature forprolonged periods, until the mixture was no longer alkaline. In some instances, special solvents, such as dialkyl carbonates, were employed. These reactions, however, generally required many hours of refluxing and resulted in a relatively expensive product. The latter is particularly true where it was necessary to prepare the dialkylated ester compounds by introducing a second alkyl group onto a carbon atom which was already monoalkylated, such as when alkylating a diethyl alkylmalonate, where heretofore it has been necessary to introduce the alkyl groups in a specific order and to use relatively expensive alkylating agents.

It is therefore an object of the present invention to provide a more economical method of introducing an aliphatic, alkenyl, aralkyl, or aryl group into an organic compound having an active hydrogen atom.

It is also an object of the present invention to provide a method of more rapidly introducing an aliphatic, an alkenyl, an aryl, or an aralkyl group into 'an organic compound having an'active hydrogen atom. a

It is stillanother object of the ,present invention to provide a more convenient method of preparing an alkylated, alkenylated, arylated, or aralkylated organic compound of the malonic ester type.

It is a still further object of the present invention to provide a more convenient and economical method of introducing a second alkyl group into a mono-substituted malonic ester.

Other objects of the present invention will be apparent from the detailed description and claims to follow.

it has now been found that if the metallo derivatives of organic compounds having an active hydrogen atom, including the more difiicultly alkylated malonic esters useful in the preparation of barbituric acid compounds, are reacted with an alkyl, alkenyl, aryl, or aralkyl halide or a dialkyl, dialkenyl, diaryl, or diaralkyl sulfate in the presence of a soluble reaction catalyst, the

reaction proceeds rapidly to completion in only a small fraction of the time required by the prior art processes,

', and without reducing the yields of the desired product wherein R is hydrogen or an organic group, R is an methylbutylrnalonic ester with ethyl bromide in the activating organic group, such as an ester, keto, cyano, or phenyl' group, M is a metal, X is an organic esterifying group, R is an alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, or aralkyl group, Y is a halogen or an alkyl sulfate, alkenyl sulfate, aryl sulfate, or aralkyl sulfate group, and RC is an alkylation reaction catalyst consisting of an organic compound devoid of active or acidic hydrogen atoms and which contain within the molecule a substantially rigid unbranched linear or curvilinear, diatomic or triatomic dipole; said dipole possessing as its negatively charged terminus, an oxygen atom with sufficient basicity and electron donor capacity, to be detectable by means of potentiometric titration with perchloric acid in acetic anhydride medium. Among the alkylation catalysts possessing the foregoing attributes and, properties. are dimethylformamide (DMF), dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), tetramethylurea, N-formylpyrrolidine, trimethylphosphine oxide, pyridine N-oxide, hexamethylphosphoramide, Nformylpiperidine, N,N-dimethylbenzamide, N- methyl-epsilon-caprolactam, N-methyl-Z-piperidone, N- methyl-Z-pyrrolidone, N-methyl-Z-pyridone. Other alkylation catalysts will, be apparent from the accompanying discussion and examples listed and set forth in the. specification.

In the case where M R'-(|]-C 0=X isa malonic ester metallo derivative, the reaction can be using the alcoholates or hydrides thereof in the same manner as sodium ethylate or sodium hydride.

In accordance with the foregoing general statement of the present invention Table I lists the relative pseudofirst-order reaction rates of alkylation at 30 of sodio-l presence of 0.648 M concentrations of various additives in a benzene solution. benzene alone is taken as unity. Also listed are the di-' pole moments of some of the additives and their. dielectric constants as measured on the pure substances.

The rate of the alkylation in TABLE I Dl- Initial Rate Con- Relative Additive electric Dipole Molarlty stant at 30 Rate Constant Moment of N X10secr (CqH5=1) deriv.

No additive (benzene solution). I. 29:1;0. 02 1. 1. (C1H5O):CO 3 0.9 0.120 1.55:1:006 1.2 2. CHJCN 39 3.2 0.123 2. 1&0. 58 1.7 3. (CH.1)CO.-.-- 21 2.8 2.0 4. (CH3)2NNO. 54 3. 98 2.2 5. a a x 36 4.0 0. 127 3 16;;0. 21 2.5 6. 25 1. 7 2.8 7. 26 3. 9 0. 127 4 13:1:0. 47 3. 2 8. 3. 3 0. 124 7 (flit). 07 5. 5 9. 3 2 27 3. 80 0.122 7 30:1;0. 40 5.8 10. (CH3)2SO 45 3 0.117 8 16:1;0. 22 6.3 11. CH;CON(CH=), 3. 87 0.123 9 98:0.08 7.3

12. HCON 0.125 10 5 $0.3 8.1

18. (CHmPO- 3.5 0. 120 13.5 it). 7 11 15. [(CHzhN'laPO- 0.119 27.8 =l=0.7

The alkylation reaction rates in Table I were determined by preparing diethyl ethyl-l-methylbutylmalonate by the procedure which comprised adding to a solution of 10 ml. of diethyl l-methylbutylmalonate in 100 ml. of dry thiophene-free benzene in a 250 ml. three-neck round bottom flask equipped with a stirrer, drying tube and nitrogen inlet tube excess (1.3-1.5 g.) sodium hydride. The reaction was allowed to stir overnight at room temperature in an atmosphere of dry nitrogen. After unreacted sodium hydride was allowed to settle, the solution of the sodium derivative was drawn by vacuum into a dry 100 ml. pipette from which the tip had been removed in order to allow for insertion of a plug of glass wool into the lower part of the stem. 7 The solution was then transferred to a nitrogen filled 125 ml. conical flask and placed in a constant temperature bath held at 30?:002".

To a 100 ml. volumetric flask containing 30 ml. of ethyl bromide previously placed in the thermostat was added either a weighed amount of the additive or a standard solution of it in benzene, the quantity being determined by the multiple of 0.324 M which was needed for the final concentration. When dimethylformamide was used as the additive, 5 ml. of the pure liquid was pipetted directly into the reaction flask to make a concentration 0.648 M (5% DMF by volume).

To this mixture was added 30 ml. of the stock solution of the sodium derivative followed immediately by enough dry benzene to make 100 ml. The solutions were then well mixed, and at intervals, 3 ml. aliquots (anywhere from 8 to 11 in all) of the reaction mixture were withdrawn by means of a pipette, added to water and titrated with 0.02 N hydrochloric acid using phenolphthalein indicator. The slope and standard deviation of the plot of the logarithm of th'e'concentra'tion of the sodium derivative against time in seconds was calculated by the statistical method of least squares. Multiplying this slope by the factor, 2.303, gave the first-order rate con stant directly.

From this Table I it is evident that there is no direct correlation of the catalytic effectiveness of these additives on the one'hand with either dielectric constant or dipole moment on the other. However, it can be seen that all of the more efiective additives do have relatively high dipole moments of 3.3 or better. It can be concluded that the presence of a dipole in the molecule is a necessary but not suflicient condition for catalytic efficiency. In other words, a particular kind of dipole must be prescut to endow the compound with catalytic properties.

kn indication of the type of dipole necessary for this action comes from an examination of the refractions of the atomic groupings which are primarily involved in the separation of electrical charges. It is generally agreed that the molar refraction of a compound or the individual bond refraction of a portion of a molecule is a measure of its electron polarizability (cf. C. P. Smyth, Dielectric Constant and Molecular Structure, Chemical Catalog Co., New York, N.Y., 1931, pages 142-168). In general, the smaller the algebraic value for the refractivity of a bond, the smaller is its electron polarizability, of, in other words, the more tightly are the electrons held which make up that bond. By making suitable measurements and calculations, the bond refractions for the C=O bond in acetone for the -C- -N bond in acetonitrile, for the -CEN bond in benzonitrile, for the S O bond indimethylsulfoxide, and for the P- O bond in trimethylphosphine oxide can be determined. These are listed in Table II. It can be seen that, al-

TABLE II Relative Bond Retractivity Catalytic Etficieney --CEN in Compound #2 of Table I +4. 77 I 1. 7

C=0.in Compound #3 of Table I +3. 46 2. 0

-05: in Compound #7 of Table '1 +5.11 3. 2

S- O in Compound #10 of Table 1..--.. +0. 74 6. 3

\ 7P- O in Compound #13 of Table I -3. 63 11 though the correlation is not quantitative, the two etfective catalysts (Compound #10 and Compound #13) I possess dipoles that are much more rigid than the three relatively ineffective ones (Compounds #2, #3 and.#7).

The same relationship holds for compounds, such as It has been calculated by L. Pauling that the contribution of the dipolar Form II (triatomic dipole) results in a stabilization of the amide linkage of the order of 20 kilocalories per mole. In other words, most amides have an energy content of the order of 20' kcal./mole less than they would if only Forms I and III were adequate representations of the resonance forms. This means that Form 11 is an important contributor to the actual structure of all amides and accounts in large part for the fact that amides possess larger dipole moments than do other carbonyl compounds such as ketones, carboxylic acids and esters.

Yet, it can be demonstrated that relative contributions of Form II can vary from one amide to another. Gutowsky and Holm [J. Chem. Phys, 25, 1228 (1956)] have shown by means of nuclear magnetic resonance studies that in different amides differing capabilities for rotation of the carbon-nitrogen bond are present. In resonance Forms I and III, rotation about the carbon-nitrogen bond is quite free since it is a single bond in both cases. be impossible because the carbon-nitrogen bond is a double bond. It would therefore be expected that with increasing contribution of Form II to the actual state .of.

themolecule, rotation about the carbon-nitrogen bond would become increasingly difiicult. Gutowsky and Holrn have shown that the barrier to rotation about the carbon-nitrogen bond in dimethylformamide seen from Table I that this is the relative order of in-i creasing catalytic activity of these two additives. Fur- However, in Form 11, such rotation would thermore. these workers found that in N-methylformani-f.

lide [HCON(CH )C H no detectable rotational energy barrier at room temperature could be perceived by their experimental method. It has been found that N- methylformanilide is a relatively ineffective alkylation catalyst.

It should be added, further, that an examination of the infrared absorption spectra of a large number of amides as well as a comparison of the measured with the calculated molar refractions of a series of amides has provided further evidence of the necessity for the presence of an unbranched, electrically rigid, linear dipole in a molecule in order to assure activity as an alkylation catalyst.

Nevertheless, a few inconsistencies in the correlation indicate that consideration of the linear dipole is not the only factor of prime importance. By introduction of another prime factor, however, the relative activities of a large number of alkylation catalysts can be fitted into a consistent, rational picture.

The most glaring inconsistency in the foregoing pici (omnihu contributes a great deal to the actual state of the molecule. This view is further consistent with the relatively high dipole moment of this substance (Table 1, Compound 4). Yet, it is a poor alkylation catalyst. The reason torthis is a lack of basicity or electron-donor capacity inthe substance.

Table 111 lists a number of compounds which were tested as catalysts in the alkylation of sodio-n-butylmalonic ester with n-butyl bromide at 25. The relative rates refer to the reaction rates measured in benzene solution containing 0.324 M (2.5% by volume for DMF) concentrations of the catalysts. As in Table I, the rate in benzene alone is arbitrarily taken as unity. In the third column of Table III are listed the half-neutralization potentials of the compounds determined by potentiometric titration with perchloric acid in acetic anhydride. It has been shown [cf. Streuli, Anal. Chem, 30, 997 (1958)] that for a number of weakly basic substances, including amides, the base strengths are inversely proportional to their half-neutralization potentials. Thus in Table III, the lower the E 1/2 the stronger the base. However, this is quantitatively true only among compounds within a given group of Table III. For technical reasons, the quantitative comparison of half-neutralizations of compounds in dififerent groups cannot be made. Some compounds in Table III are such weak bases that titrations produce only smooth curves. In these cases end-points are undetectable and half-neutralization potentials cannot be determined. For these nonbasic compounds, the words No break are placed in the third column.

TABLE III Additive (0.324 M cone.) Relative E 1/2 (mv.)

. Rate Group A:

1 (CHmNNO 1.9 No break. 2 HGON(C5H )Z 3.0 Do. 3 HCON(CH3)C5H5 2.6 DO. 4 (OHmNCOOGHz 1-2 Do. 5 (OHmNCN 11.5 623. 6. (CH:1)2NCON(CH3 6-7 546. 7. HCONtCH 7.0 625. 8. CH3OON(CH3)1 8.7 530. Group B:

9. CH,CON b 4.6 546.

10. HCON E) 4.6 564.

11. HCON 6.0 553.

12. HCON 9.7 536. L Group C:

13. CF3CON(CH3)1 1.7 No break. 14. (CH3)3CCON(CH3) 4.1 460. 15. CflH5CON(CH3)2--- 6.2 438.

O ll 18. N-CH: 11.0 405.

Group D:

(8). CHsCON(CHa)z 8.7 462. 19. [(CHmNkPO 54 450. Group E:

20. 1-2 No break.

21. (01 10180 15 476. 22. (CHs)sP0 2530 431. Group F:

NCH: 16 466.

Examination of Table III reveals that, with the single exception of dimethylcyanamide (Compound of all the catalyststhat exhibit demonstrable basicity, even the least effective ones are more active than the additives 8 even qualitatively correlated with catalytic activities. In these cases, however, detailed consideration of both linear dipoles and basicity of the oxygen atom at the negative terminus of the dipole lead to a consistent, rational picwhich possess no measurable basicity whatsoever. The 5 ture for all the alkylation catalysts. reason for the inactivity of dimethylcyanamide is that The measured rate constants for the alkylation of sodioits dipole is restricted to the cyano group, which is not a n-butylmalonic ester with n-butyl bromide according to rigid dipole. In other words for a triatomic dipole to the general procedure given following Table I at 25 C. be present, contribution from the form, and 37.44 C. at the specified concentrations with several alkylation catalytic additives are listed in Table IV. I; The numbers in parentheses denote rate of alkylation I 7 relative to that found 1n the absence of additlve at the would have to be important. From considerations of corresponding temperature. 'The additives are grouped structural theory, this is unlikely. according to common structural resemblance. Multi- More detailed examination of Table III by groups ple measurements under identical conditions are either shows that, in many cases, relative basicities cannot be averaged or, where possible, statistically pooled.

TABLE IV Additive (A) Cone. of A k X10 Sec.- k"- 10 see.-

( Av- Av) No Additive A. Formamide Derivatives 5.s7.10 5. 23. 09 14. 14 5. 81. 00 13. 05. 13. 5. 84. 10 14. 13. 11 5. 403:. 16 14. 605:. 17 l 6. 02. 1O. 13. 065: 13

HO ON(CH;)1 0. 04s 15.43 30 43.51.04 HCON(CH;)| 0. 54s 15. 02 47 43.3.92

HCON 0.324

Ho ON 0. 324 7. 79. 07 20. 1 2

HCON 0. 324 s.7s.15 21. 4. 0s

HCON 0. 324 4. 67. 07

HGON 0. 324 5. 32. 13 12. 2. 13

He ON 6 0. 324 3. 68. 02 9. 93. 07

HCON b o. 324 3. 04.04' 9.97. 07

B. Dimethylacetamide and Variants 01110 011mm), 0. 324 7. 43.- 0s .........5 CH C ON(CH|)= 0. 324 7. 05. 05

CHaC ON(CHr)z 0. 648 18. 95:. 6

See footnote at end of table.

TABLE IV-Continued Addltivo (A) (June. of A M'Xll) sec: l== 1o= sec.-

( Av. Av.

cmc ON 6 0.324 3.s3=|=.o5 (4.5)

OHaCSN b 0.324 3 76:k.30 (4.6)

OHmCCONwH) 0.324 8 41:1; 05 4.1) icllmccomcnifiuu 0. 648 9 1332.09 (11 0. Cyclic Amides \N L0 0. 54s 5.14=1=.11 (e. 2) 12.05:. a (a. 0)

1:0 0. 648 22. 21b. 6 53. 2&2. 4 \N 1 0. 54s 27. 3.11:. s 61. 4i1. 6

\N/=O U. 324 9- 045:. 11

. 0 0.324 12. 92:0. 3 15 34. 411. 5 (16) 0. (14s 49. 511.4 (60) 138i3 55) (SH. 5

F. Miscellaheous Additives mmoomcm o. 324 5141.04 5. 2) 011150 ON(CH3)5 0. 5 18 14.71.19 (13) [(0113) :NIaP O 0. 324 44. 9:1. 4 (54) 111:53 (53) N;6 o. 324 15. 15. 2 1s 4s. 3:119 21 See footnote at end of table.

TABLE IV-Continued b The number in parentheses after the average rate constant is the relative rate compared to the average rate at the given temperature in the absence of additive, i.e., relative Rate constant for the first 35% of reaction. Between 35% and 60% of reaction, k=0.54:l:0.0l lsec.- d Rate constant for the first 35% of reaction. Between 35% and 60% of reaction. Ic =0 53i00l secr Rate constant for the first part of the reaction. The rate was not measured after 35% of completion. k=1.18:l:0.08X10' sec.- 1.34i0.05 10- sec.-

1 Rate constant for the first or reaction. After 20% reaction,

a Rate constant for the first 20% of reaction. After 20%, k Rate constants for two runs using 0.324 M DMF at 15 C were I The statistically pooled value rather than the average was used for calculation of the thermodynamic functions. I After a lapse of 18 months. a check run using 0.324 M DMF gave k =5.3$: i=.07x11--scc.' is After a lapse of 19 months, a check run using 0.324 M N-methylformnnilide gave k =2.24;l=.l9

lfl' secr 4.88:l=0.09, and 5.17:L-0.09X10- sec.' (average=5.19).

In the following specific examples are shown several specific embodiments of the present invention but it should be understood that the invention is not to be limited to the specific reactions disclosed nor to the precise proportions or conditions set forth in the several specific examples, since the examples are given only for the purpose of illustrating the principle of the present invention.

EXAMPLE 1 Dierhyl ethyl-1-methylbutylmalonate ed to the cooled residual solution and the solution heated to distill off the remaining ethyl alcohol in vacuo. The dimethylformamide solution is then cooled to l0-20 C.

1 Rate constants for three runs using 0.324 M (CHmSO at 15 were 5.52:b0.12,

and ethyl chloride, 16 pounds, is added from a dropping tank. The system is then closed and the solutionheated to a temperature of about 115 C. and maintained at the said temperature for about five hours. Thereaction mixture is then cooled and dimethylformamidc is removed'under vacuum up to a still temperature of 115 C. under a vacuum of 27-275 inches. The reaction mixture is cooled and six gallons of water is added with agitation, followed by 4-6 gallons of benzene. The two layers are allowed to separate and the clear water layer is drawn oif. An additional six gallons of water is added, agitated, and separated in the same manner. Most of the benzene is removed by distillation at atmospheric pressure and the final traces of benzene removed in vacuo. The product diethyl ethyl1-methylbutylmalonate distills at a temperature of 144-146 Cast a pressure of 20 mm. mercury to provide a yield of 86.6% theory which assays 97.5% pure. The said product ex hibits an index of refraction 11 1.4352.

Specific Examples 2 through 26 using dimethylform amide were conducted according to the same procedure as described in Example 1 and in Table V are set forth in the reactants used, resulting reaction product, time of reacting, and yields obtained.

TABLE V Example Starting Ester Alkylating Agent Reaction Product Reaction Yield,

No. Time Percent 2 Dlethyl Inalonate l-Methyl-butyl bromide Dlethyl l-methyl-butyl-malonate 2 111-5-.-- 82. 7 3 Diethyl l-methyl-butyl-mslonate- Diethyl sulfate Diethyl ethyl-l-methyl-butyl-malo- 16 min.- 84. 6 nate. 4 do Allyl-chloride Dietthyl allyl-l-methyl-butyl-malo- 20 min 78' na e. DlethylA cyclo-hexenyl-malonate do Dletiiyl allyl-N-cyclo-hexenyl-malc- Lfihrs..- 81

. na e. Dlethyl malonate. do Diethyl allyl-malonate 1.5 hrsh 1Not 0 ated Diethyl allyl-malnn'ite rio Dlethyl dlallyl-malonate. 15 min.. 67 Diethyl-malonate Isopropyl bromide Diethyl isopropyl-malonate- 1 hr..- 84 Diethyl isopropyl-malonate- Diethyl sulfate..- Diethyl ethyl-isopropyl-malonate. 20 min- 78. 5 Diethyl mztlonate sec-butyl bromide Diethyl sec -butyl-mal0nate 1.5 hr|.. '90 Diethyl sec-butyl-malonate Ethylchloride Diethyl sec -butyl-ethyl-malonate.. 5 hrs- 90. Diethylmalonate Diethyl n-butyl-malonate 8 min 73' Diethyl n-butyl-malonate- Diethyl n-butylethyl-malonate- 10 min 90 Diethyl malonate Diethyl lsoamyl-malonate 30 min 77. 2 Diethyl isoamyl-malonate Dlethyl isoamyl-ethyl-rnalonate 10 min- 90 Diethyl henzyl-malonate. Diethyl dibenzyl-malonate 1 hr..... 75 Ethyl a-ethyl acetoacetate 1 n-Propyl bromide Ethyl a-ethyl-a-n-propyl-acetoaoe- 3 hrs.... 63

a e. Ethyl acetoacetate 1 Isopropyl bromide Ethyl a-isopropyl-acetoacetate min- 61. 8 Ethyl a-cthyl acetoacetate Ethyl a-ethyl-a-benzyl-acetoacetate 3 hrs 62. 6 Ethyl acetone-dlcarhoxylate -Diethyl a-Inethyl-B-keto-glutarate- 30 min- 23 Ethyl cyano-acetate Ethyl a-cyano-B-methyl-valerate. 15 min- 72.5 Ethyl a-cyano-;S-methyl-valerate Ethyl bromide Ethyl Ex-cyano-a-ethyl-fi-methyl- 1.5 hrs-.. 88

' va era e. Diethyl isopropyl-malonate Ethyl-chloride Diethyl ethyl-isopropyl-malonate... 5 hrs.... 86 Dlethyl Y do Diethyl n-butylethyl-malonate 5 hrs.... 7 90 Dlethyl lsoamyl-malon' te do Diethyl isoamyl-ethyl-malonste 6 1111's.... 88 Diethyl-phenyl-malonam do Diethyl ethyl-phenyl-malonate 5 hrs... 91*

1 Sodium salt made by reaction with suspension of sodium hydride instead of using sodium metal procedure as in Example 1. 1 Sodium salt made by reaction with suspension of sodium hydroxide instead of using sodium metal procedure asln Example -1- Comparable yields of the alkylatedproductsloffthe preceding Examples 1 through 26 are producedby following the sameprocedure but using dimethylacetamide in place of dimethylformamide as the alkylation catalyst. The following examples illustrate the alkylation reaction using dimethylacetamide as the catalyst.

EXAMPLE27 Diethyl ethyl-1-methylbutylmalonate An alcoholic solution'of sodium ethylate is prepared by reacting 23.7 g. of sodium metal with 300 cc. of ethyl alcohol, and 230.3 g. of diethyl l-methylbutylmalonate is added with stirring to the said sodium ethylate solution at 65-75 C. to form an alcoholic solution of the sodio derivative of diethyl l-methylbutylmalonate. Most of the alcohol is distilled in vacuo and 250 cc of dimethylacetamideis added. The remaining ethyl alcohol is removed in vacuo. Thereafter, 120 g. of ethyl bromide is added at 3040 C. over a -minute period. The reaction temperature is allowed to, rise exothermically to 100 C. and then held between about 90-100 C. for 20 minutes. The temperature is allowed to cool to 60 C. whereupon the ,dimethylacetamide is removed in vacuo. The residual mixture is neutralized with acetic acid and 250 cc. of water is added. The ester'phase is extracted with benzene and the benzene extract washed once with 100 cc. of water, The benzene is removed by distillation and the crude ester fractionated in vacuo. The product diethyl ethyl-l-methylbutyimalonate d ist ills at a temperature of 143-l45 C. at a pressure of 20 mm. mercury to provide a yield of 84% theory whichassays The following examples illustrate the alkylation reaction using dimethylsulfoxide: EXAMPLE 37 Diethyl ethyl-1-melhylbutylmalonate A solution of sodium ethylate is prepared by reacting 300 cc. of ethyl alcohol with 23.46 grams of sodium metal. Distilled diethyl l-methylbutylmalonate, 230 g., is added to the sodium ethylate solution with stirring at I '5075 C. over a 15-minute period to form the sodioderivative of diethyl l-methylbutylmalonateg Most of the alcohol is removed by distilling in vacuo (100-150 mm.) and dimethylsulfoxide, 250- cc.,'is added. The remaining alcohol. is removed. in vacuo and the dimethylsulfoxide solution transferred to a 1-liter, stainlesssteel bomb. The dimethylsulfoxide solution is heated to 115- 120 C. and ethyl chloride, 77 g., is forced in under pressure over a /2-110111' period. The contents of the bomb are heated at 115-120" ,C. for five hours, then cooled and the dimethylsulfoxide removed in vacuo. The residual ester-sodium chloride mixture is treated with 250 cc. of water and the ester layer extracted with benzene. The benzene solution is concentrated and the ester fractionated. The yield of diethyl ethyl-l-methylbutylmalonate is 85-86% of theory. This material has a boiling point of 144-146 C. at a pressure of 20 mm. mercury and exhibits an index of refraction n 1.4352.

Specific Examples 38 through using dimethylsulfoxide were conducted according to the same procedure as described, in Example 1 and in Table VII are set forth the reactants used, resulting reaction product, time of reaction, and yield obtained:

ABLE VI! Starting Ester Aikyl ating Agent Reaction Product Reaction Yield,

- r "Iime Percent Diethylmalonate i'methyl-butyl bromide Diethyl1-methyl-butyl-malonate 2mm. 84 Diethyl l-methyl-butyl-malonate--- Allyl-chlorlde Diethyl allyl-l-methyl-butyl-malo- 20 min- 76 r r nate. Diethyl henzyl-malonate Benzyl-chloride.--. Diethyl dibenzyl-malonate 1 hr 75 Ethyl q-ethyl aceto-acetate n-Propyl bromide Etthtyi wethyl-a-n-propyl-aceto-ace- 3hrs 60 r i r 1 a e. Ethyl methyl aceto-aeetate Benzylbromide Etthyla-ethyha-benzyhaceto-ace- 3hrs 60 a e. Ethyl acetodicarboxylate Methyl indida Diethyl a-met-hyl-B-keto-glutarate.-- 30 min 25 Ethyleyano-acetate sec-Butylhromide Ethyl-a-cyano-fl-methyl-valerate. 15min 72 Ethyla-eyanofl-methyl-valerate- Ethylbromide Ethyla-cyano-a-ethyl-fl-methyl-val- 1.51m..- 87

. crate.

1 Sodium salt made by reaction with suspension of sodium hydride instead of usingusgodium metal procedure as in Example 1.

I Sodium salt made by reaction with suspension of sodium hydrozide instead of us The said product exhibits an index of re-.

96.7% pure. fraction #15 1.4350.

Specific Examples 28 through 36 using dimethylacetamide were conducted according tothe same procedure as described in Example 1 and in Table VI areset forth the reactants used, resulting reaction product, time of sodium metal procedure as in Example 1.

i EXAMPLE 46 Diethyl ethyl-1-methylbutylmalonate i The sodio derivative of diethyl l-methylbutylmalonate is prepared by slowly adding diethyl l-methylbutylmalonate, 23 g. (0.1 m.), to a suspension of sodium hyreaction, and yield obtained; L dride, 2.4 g. (0.1 m.), in 150 ml. of dry benzene at i i TABLE VI Example Starting Ester g AlkylatingAgent Reaction Product Reaction Yield,

N0. Time Percent Diethylmalonate; i-methyl-butylbromide----;.-, Diethyll-methyl-butyi-malonate- 2hrsso Diethyl l-methyl-butyl-malonate-. Aliyl-chlorlde s Diethyl allyl-l-methyl-butyl-malo- 20 min 75 nae.

Diethyl-benzyl-malonate Benzyl-chlorida; Diethyl-dibenzyl-malonate 11111-.-. 76 Ethyl a-ethyl acetoacetate n-Propyl bromide. Eghtyl acthyLa-n-propyI-aeemace- 3hrs t a e. Ethyl acetoacetate Isopropyl-bromide Ethyla-isopropyl-acetoacetate 90111111.. 61 Ethyl wethylacetoacetate Benzyl-bromide. Ethyl a-ethyi-a-benzyl-aoetoacetate Ehrs-- 62 Ethylacetone-dicarboxylate' Methyliodide Diethyl amethyl-B-keto-glutarate--- 30 min.. -26 Ethyl cyano-acetate sec-butyl-bromide- Ethyl a-cyano-fi-methyl-vaierate.-.- 15 min Ethyl a-cyano-flmethyl-valerate.-.. Ethyl bromide; Ethyl at-cyano-a-ethyl')8 methyl- 1.5hrs... 85 r. i I p t I va are e.

, i 1 Sodium salt made by reaction with suspension of sodium hydride instead of using sodium metal procedure as in Example 1. I Sodium salt made by reaction with suspension of sodiumihydroxide instead of using sodium metal procedure as in Example 1.

Comparable yields of the alkylated products of Examples 1 through 26 can also be obtained by following the procedure specified in the said examples wherein diroom temperature. As soon as the reaction, is complete pyridine N- oxide, 10 gr., is added to the solution of the said sodio derivative followed by 11g. .(0.l in.) of

methylsu-lfoxide isused in place of dimethylfor mamide. ethyl bromide. The mixture is then heated for about amasthree hour G OIQ and sod um brom e s a me by filtering the reaction mixture. The solvent is removed by distillation, the residue is treated with water, the organic phase extracted with ether, and the ether solution is dried over sodium sulfate. Thesolution is then concentrated to remove the solvent and distilled under vacuum 'to obtain the product diethyl ethyl-l-methylbutyl'rnalonate which boils at a temperature of'144- -l46 C. at a pressure of mm. mercury and exhibits a refractive index 11 1.4352. Trimethylphosphine oxide being a solid, is also used in a solvent, such as benzene, in the same manner as pyridine N-oxide of Example 46. And, as is evident from the date in the tables, both pyridine N-oxide and trimethylphosphine oxide are also very efiicient catalysts for ethylating diethyl l-methylbutylmalonate.

AMPLE 4 .Diethyl ethyl-1-mgthylbutylmal0nate A solution of sodium ethylate is prepared byreacting 300 cc. of ethyl alcohol with 23.0 g. of sodium metal. Distilled diethyl l-methylbutylmalonfle: 230.3 g., is add. ed to the sodium ethylate solution with stirring at 50.75 C. over a 15-minute period to form the sodio derivative of diethyl l-methylbutylmalonate. Hexamethylphosphoramide, 200 cc., is added to the foregoing solution and ethyl alcohol removed by distilling in'vacuo; Ethyl bromide, g., is added at 20 C. over av 15-minute period with cooling. After the addition is completed, the mixtureis heated to about 110 C. andmaintained at said temperature for about 9.0 minutes. The reaction mixture is cooled and a suflicient quantity of water and benzene is added with agitation. Two layers are allowed to separate and the clear Water layer drawn olr.

An additional amount of water is added, agitated, and

sodio derivative of diethyl malonate.

samba/easy assume at atmospheric pressure and th e j j final traces of benzene removed in vacuo. The product i diethyl ethyl-1-methylbutylmalonate distills at a temperaatatmospheric pressure up to a still temperature of about 115-420 C. to remove most of the ethyl alcohol. Thereafteny the residual solution is cooled to a temperature or 4 050 C. N-methyI-Z-pyrrolid ne,140 cc., is then added to the cooled residualsolution and the solution heatedjg distill off thezremaining ethyl alcohol in vacuo. The N-methyl-Z-pyrrolidone solution is then cooled to 10 20 C. and ethyl bromide, grams, is added from a dropping tank. The system is then closed; and the solution heated to a temperature of about 115 C. and maintained at the said temperature for about five hours. The reaction mixture is then cooled and catalyst is removed under vacuum. The reaction mixture is cooled and water is added with agitation, followed by benzene. Two layers are allowed to separate and the clear water layer is drawn off. An additional amount of water is added, agitated, and'separated in the same manner. Most or the benzene is removed by distillation at atmospheric pressure and the final traces of benzene removed in vacuo. The product diethyl ethyl-l-methylbutylmalonate distills at a temperature of 144-146 C. at a pressure of 20 mm. mercury.

EXAMPLE 5O Diethyl l-m ethylbutylmalonate A solution of sodium ethylate is prepared by reacting 300 cc. of ethyl alcohol and 23.0 g. of sodium metal; Redistilled diethyl malonate, 160 g., is added with stirring to the-said sodium ethylate solution at 75 C. over 'a 15-minute period to form an alcoholic solution of the -m t Y -Z-W done, 200 cc., is added to the lattersolution with ooqling and the resulting solution is concentrated in vacuo to i remove ethanol. The residual solution is heated to C.

and l-methylbutyl bromide, 158 g;, is added over a 15- minute period. Sodium bromide starts to separate after theadditionis .completed, the reaction IIltiXillfe iS heated ,..to C. The temperature rises spontaneously to about ture of 1444146 C; at a pressure of 20 mm. memory,

EXAMPLE 48 Dithyl n-butylmalanate n V H A solution of sodium ethylate is prepared by reacting .750 ccof e hyl al o ol and .8- o d m metaL.

Redistilled diethyl malonate, 400.5 g., isadded to the sodium ethylate solution with stirring at a temperature of 50-75 C. over a 20-minute period. N-methyl-epsiloncaprolactam, 400 cc., is added .to the foregoing solution and ethyl alcohol removed by distilling in vacuo. To the foregoing solution is added n-butyl bromide, 360 g., at a temperature of 85--90 C. over a 10-minute period with cooling. -The reaction mixture is held at a temperature of 85-90 C, for about seven minutes without external heating and thereafter is heated to 100 C. and held at C. and remains at that temperature for 10 minutes before receding. 'The temperature is maintained at 1153 C. for 2 hours, then glacial acetic acid is added to neutralize the reaction mixture. The N-methyl-2-pyridone is distilled in vacuo and the residue is treated .withwater,

.said temperature for about eight minutes. Thereafter, the

reaction mixture is neutralized with acetic acid and the N-methyl-e-caprolactam removed by distilling in vacuo.

Water is then added and'the organic ester phaseis separated and the aqueous phase extraeted-with ether, dried, and concentrated on a steam bath. The crude ester phase and the ether concentrate are distilled to yield diethyl n-butylmalonate which boils at a temperature of 114-117" C. at a pressure of -10-mm.; mercury. The product exhibits a"refrac tiye index 11 1.4216.

EXAMPLE 49 Diethyl ethyl-1-methylbutylmalonare amet iiclbutylmal nate' The reactiq mixmr isdistilledg 200 cc., and the organic layer extracted withether (or benzene). The extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude-product diethyl 1-methylbutylnaalonate distills at a temperature vof B l-133 Q. ata pressure of 20mm. mercury and exhibits a refractive index of'n 1.422

I w be app r n om he e o ng sn i samp that .the present invention is particularly useful in making it possible to introduce very readily. an allryllgroup into a malenic ester, even those which are already substituted by a hydrocarbon substituent group, such as a monocyclic aryl, an alkyl, an alkenyl, a cycloalkenyl, or an aralkyl group; thereby enabling substituted malonic esters and in similar compounds useful for the preparation of barbituric acid derivatives to be prepared much more readily and more economically than heretofore.v Thus, for example, it is v11.0w commercia lr q ibl to intrqduse first he larger alkyl group, such as the l-methylbutyl grannies a ph nv o p. in n un s t d malonis si s- 1 w th q without using-the reaction solvent alkylation catalyst, and

easily recoyer the desired mono-substituted malonie ester p odu t in ar i y P e orm n thereafter introduce the l er a y p, s ch as he ethyl o p opyl sm g, into the said mono-substituted malonic ester product by means of the preferred embodiment of the herein disclosed pr ess us n thy sh de a th alky t ns en n a actio'n medium comprising one of the herein disclosed reasflqn lkylat aa ca al sts. u h m hv io m d or, idai d wi hth dim thrlf m mids m xes i h aniasr solvent, such as benzene, toluene or xylene. The" latter allrylation reaction proceeds to oompletion rapidly produces the desired di-substituted malonic ester in very high yields. The foregoing is in marked contrast with the procedures heretofore required wherein under commercial conditions it has been necessary to introduce first the smaller of the two alkyl substituents, for example, into the said malonic ester by prolonged heating of the alkyl bromide or dialkyl sulfate with the result that a very substantial proportion of dialkyl product is formed which makes it extremely diflicult to recover the desired monoalkylated product directly from the reaction mixture in a pure form. Heretofore, the second larger alkyl group was then introduced into the mono-alkylated malonic ester only after prolonged heating with one of the more active alkylating agents, such as the alkyl bromide or dialkyl sulfate; and could not be introduced commercially by heating with the less reactive and less expensive alkyl chlorides. It will thus be apparent that the present invention greatly shortens and simplifies the preparation of many malonic ester compounds which are suitable for use in the manufacture of barbituric acid derivatives having wide pharmaceutical utility as anesthetics and hypnotics.

In the specification and claims, the term alkylating agent is used to designate a compound capable of replacing a hydrogen or metallo atom of an organic compound with an acyclic or alicyclic aliphatic group and including such compounds as the alkyl, cycloalkyl, alkenyl, cycloalkenyl, and aralkyl halides and disulfates. Because of their relatively low cost, the alkyl halides, and particularly the lower alkyl chlorides, such as ethyl chloride or propyl chloride, are the preferred alkylating agents of the present invention which makes for the first time the use of the less reactive alkyl chlorides commercially possible. It should be understood, however, that the other halides, such as the alkyl bromides and iodides, and the said disulfates, such as dialkyl sulfate, dialkenyl sulfate, and diaralkyl sulfate, are also suitable for use in the present invention, if desired.

The present application is a continuation-in-part application of our co-pending patent applications Serial No. 512,878, filed June 2, 1955; Serial No. 517,932, filed June 24, 1955; and Serial No. 566,096, filed February 17, 1956. All the foregoing applications have now been abandoned.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed or equivalents thereof. As at present advised with respect to the apparent scope of our invention, we desire to claim the following subject matter.

We claim:

1. A method of introducing a radical selected from the group consisting of loweralkyl and benzyl into an ester selected from the group consisting of diloweralkyl malonates,lowera1kyl acetoacetates and loweralkyl cyanoacetates which comprises reacting an alkali metal salt of said ester with a member of the group consisting of loweralkyl chlorides, loweralkyl bromides, loweralkyl iodides, benzyl chloride, benzyl bromide, benzyl iodide, diloweralkyl sulfates and dibenzylsulfate in the presence of a catalyst selected from the group consisting of tetrarnethylurea, N-formylpyrrolidine, trimethylphosphine oxide, pyridine N-oxide, hex'amethylphosphoramide, N-

formylpiperidine, N,N-dimethylbenzamide,' N-methylepsilon-caprolactam, N-methyl-Z-piperidone, N-methyl- Z-pyrrolidone and N-methyl-2-pyridone.

2. A method for the preparation of diethyl ethyl-1- methylbutylmalonate which comprises reacting equimolar quantities of sodium diethyl l-methylbutylmalonate and ethyl bromide in the presence of a catalytic amount of pyridine N-oxide.

3. A method for the preparation of diethyl ethyl-1- methylbutylmalonate which comprises reacting equimolar quantities of sodium diethyl-l-methylbutylmalonate and ethyl bromide in the presence of a catalytic amount of trimethylphosphine oxide.

4. A method for the preparation of diethyl ethyl-1- methylbutylmalonate which comprises reacting equimolar quantities of sodium diethyl-l-methylbutylmalonate and ethyl bromide in the presence of a catalytic amount of hexamethylphosphoram'ide.

5. A method for the preparation of diethyl ethyl-1- methylbutylmalonate which comprises reacting equimolar quantities of sodium diethyl-l-methylbutylmalonate and ethyl bromide in the presence of a catalytic amount of N- methyl-Z-pyrrolidone.

6. A method for the preparation of diethyl-n-butylmalonate which comprises reacting equimolar quantities of sodium diethylmalonate and n-butyl bromide in the presence of a catalytic amount of N methyl-epsiloncaprolactam.

7. A method for the preparation of diethyl l-methylbutylmalonate which comprises reacting equimolar quan tities of sodium diethylmalonate and l-methylbutyl bromide in the presence of a catalytic amount of N-methyl-2- pyridone.

References Cited in the file of this patent UNITED STATES PATENTS 2,365,898 Morris et a1 Dec. 26, 1944 2,438,241 Wallingford et a1. Mar. 23, 1948 2,812,324 Huber et al Nov. 5, 1957 OTHER REFERENCES Hoffman: J. Org. Chem. 15, 425-434 (1950). Fuson: Advanced Organic Chemistry, 1950, pages 413-415 and 418-422.

Shapira et al.: J. Am. Chem. Soc. 75, 3655-7 (1953). 

1. A METHOD OF INTRODUCING A RADICAL SELECTED FROM THE GROUP CONSISTING OF LOWERALKYL AND BENZYL INTO AN ESTER SELECTED FROM THE GROUP CONSISTING OF DILOWERALKYL MALONATES, LOWERALKYL ACETOACETATES AND LOWERALKYL CYANOACETATES WHICH COMPRISES REACTING AN ALKALI METAL SALT OF SAID ESTER WITH A MEMBER OF THE GROUP CONSISTING OF LOWERALKYL CHLORIDES, LOWERALKYL BROMIDES, LOWERALKYL IODIDES, BENZYL CHLORIDE, BENZYL BROMIDE, BENZYL IODIDE, DILOWERALKYL SULFATES AND DIBENYLSULFATE IN THE PRESENCE OF A CATALYST SELECTED FROM THE GROUP CONSISTING OF TETRAMETHYLUREA, N-FORMYLPYRROLIDINE, TRIMETHYLPHOSPHINE OXIDE, PYRIDINE N-OXIDE, HEXAMETHYLPHOSPHORAMIDE, NFORMYLPIPERIDINE, N-N-DIMETHYLBENZAMIDE, N-METHYLEPSILON-CAPROLACTAM, N-METHYL-2-PIPERIDONE, N-METHYL2-PYRROLIDONE AND N-METHYL-2-PYRIDONE. 